Daryl A. Guthrie

Development of N-Substituted Hydroxylamines as Efficient Nitroxyl (HNO) Donors

Due to its inherent reactivity, nitroxyl (HNO), must be generated in situ through the use of donor compounds, but very few physiologically useful HNO donors exist. Novel N-substituted hydroxylamines with carbon-based leaving groups have been synthesized, and their structures confirmed by X-ray crystallography. These compounds generate HNO under nonenzymatic, physiological conditions, with the rate and amount of HNO released being dependent mainly on the nature of the leaving group. A barbituric acid and a pyrazolone derivative have been developed as efficient HNO donors with half-lives at pH 7.4, 37 °C of 0.7 and 9.5 min, respectively.

“Catch-and-Release” of HNO with Pyrazolones

A new and versatile class of HNO donors, the (hydroxylamino)pyrazolone (HAPY) series of HNO donors utilizing pyrazolone (PY) leaving groups, is described. HNO, the smallest N-based aldehyde equivalent, is used as a reagent along with a variety of PY compounds to synthesize the desired HAPY donors in what can be considered an N-selective HNO-aldol reaction in up to quantitative yields. The bimolecular rate constant of HNO with PY in pH 7.4 phosphate buffer at 37 °C can reach 8 × 10(5) M(-1) s(-1). In (1)H NMR experiments, the HAPY compounds generate HNO quantitatively (trapped as a phosphine aza-ylide) with half-lives spanning 3 orders of magnitude (minutes to days) under physiologically relevant conditions. B3LYP/6-31G* calculations confirm the energetically favorable reactions between HNO and the PY enol and enolate, whereas HNO release is expected to occur through the oxyanion (OHN-PY) of each HAPY compound. HNO has been shown to provide functional support to failing hearts.

Curtailing the Hydroxylaminobarbituric Acid–Hydantoin Rearrangement To Favor HNO Generation

Due to its inherent reactivity, HNO must be generated in situ through the use of donor compounds. One of the primary strategies for the development of new HNO donors has been modifying hydroxylamines with good leaving groups. A recent example of this strategy is the (hydroxylamino)barbituric acid (HABA) class of HNO donors. In this case, however, an undesired intramolecular rearrangement pathway to the corresponding hydantoin derivative competes with HNO formation, particularly in the absence of chemical traps for HNO. This competitive non-HNO-producing pathway has restricted the development of the HABA class to examples with fast HNO release profiles at physiological pH and temperature (t(1/2) < 1 min). Herein, the factors that favor the rearrangement pathway have been examined and two independent strategies that protect against rearrangement to favor HNO generation have been developed. The timecourse and stoichiometry for the in vitro conversion of these compounds to HNO (trapped as a phosphine aza-ylide) and the corresponding barbituric acid (BA) byproduct have been determined by (1)H NMR spectroscopy under physiologically relevant conditions. These results confirm the successful extension of the HABA class of pure HNO donors with half-lives at pH 7.4, 37 °C ranging from 19 to 107 min.

Conformation as a Protecting Group: A Regioselective Aromatic Bromination En Route to Complex π-Electron Systems

A new strategy to achieve regioselective functionalization of a sterically congested aromatic system driven by conformational demands is described. Electrophilic substitution occurs at the more planarizable subunit without undesired chemistry at mutually reactive sites and without the need for protecting or masking groups that must be manipulated later. Model studies are described to understand this selectivity, and possibilities for the construction of orthogonal, differentially substituted pi-systems of relevance for molecular electronics are demonstrated.

Conformationally Complex π-Conjugated Molecular and Polymeric Materials: New Challenges for Organic Synthesis

Conformational influences profoundly impact the performance of organic electronic materials and the reactivity of organic molecules. We recently found that the expected former consideration was uniquely accompanied by the latter. This report describes a surprisingly regioselective bromination that suggests the general use of conformation as a protecting group during complex molecule synthesis.

Hydroxylamines With Organic-Based Leaving Groups as HNO Donors

Due to its inherent reactivity, HNO (azanone, nitroxyl) must be generated in situ through the use of donor compounds. One of the most fruitful strategies for the development of new HNO donors has been the use of hydroxylamines modified with good leaving groups. Classic examples of this strategy are Piloty’s acid and its derivatives, with sulfinate leaving groups, and N -hydroxycyanamide, with a carbon-bound leaving group (cyanide). More recently, alternative N -substituted hydroxylamines with carbon-bound leaving groups based on Meldrum’s acid, barbituric acid, and pyrazolone scaffolds have been synthesized and examined. These donors are capable of releasing HNO quantitatively without enzymatic activation under physiological conditions with half-lives ranging from minutes to hours.